Process for the Manufacture of fused piperazin-2-one derivatives

ABSTRACT

Disclosed are processes for the preparation of fused piperazin-2-one derivatives of general formula (I)  
                 
 
wherein the groups R 1  to R 5 , A 1  and A 2  have the meanings given in the claims and in the description, particularly the preparation of 7,8-dihydro-5H-pteridin-6-one derivatives and intermediates thereof.

APPLICATION DATA

This application is a divisional application of U.S. application Ser.No. 11/284,836 filed Nov. 22, 2005 which claims priority to Germanapplication DE 10 2004 058 337 filed Dec. 02, 2004, both of which areincorporated herein in their entirety by reference.

The invention relates to a process for preparing fused piperazin-2-onederivatives of general formula (I)

wherein the groups R¹ to R⁵ have the meanings given in the claims andspecification, particularly a process for preparing7,8-dihydro-5H-pteridin-6-one derivatives.

BACKGROUND TO THE INVENTION

Pteridinone derivatives are known from the prior art as activesubstances with an antiproliferative activity. WO 03/020722 describesthe use of dihydropteridinone derivatives for the treatment of tumoraldiseases and processes for preparing them.

7,8-Dihydro-5H-pteridin-6-one derivatives of formula (I) are importantintermediate products in the synthesis of these active substances. Uptill now they have been prepared using methods involving reduction ofnitro compounds of formula (II) below, which led to strongly colouredproduct mixtures and required laborious working up and purificationprocesses.

WO 96/36597 describes the catalytic hydrogenation of nitro compoundsusing noble metal catalysts with the addition of a vanadium compound,while disclosing as end products free amines, but no lactams.

The aim of the present invention is to provide an improved process forpreparing compounds of formula (I), particularly7,8-dihydro-5H-pteridin-6-one derivatives.

DETAILED DESCRIPTION OF THE INVENTION

The present invention solves the problem outlined above by the method ofsynthesising compounds of formula (I) described hereinafter.

The invention thus relates to a process for preparing compounds ofgeneral formula I

wherein

-   -   R¹ denotes a group selected from the group consisting of        chlorine, fluorine, bromine, methanesulphonyl, ethanesulphonyl,        trifluoromethanesulphonyl, para-toluenesulphonyl, CH₃S(═O)— and        phenylS(═O)—    -   R² denotes hydrogen or C₁-C₃-alkyl,    -   R³ denotes hydrogen or a group selected from the group        consisting of optionally substituted C₁-C₁₂-alkyl,        C₂-C₁₂-alkenyl, C₂-C₁₂-alkynyl and C₆-C₁₄-aryl, or a group        selected from the group consisting of optionally substituted        and/or bridged C₃-C₁₂-cycloalkyl, C₃-C₁₂-cycloalkenyl,        C₇-C₁₂-polycycloalkyl, C₇-C₁₂-polycycloalkenyl,        C₅-C₁₂-spirocycloalkyl and saturated or unsaturated        C₃-C₁₂-heterocycloalkyl, which contains 1 to 2 heteroatoms,    -   R⁴, R⁵ which may be identical or different denote hydrogen or        optionally substituted C₁-C₆-alkyl, or    -   R⁴ and R⁵ together denote a 2- to 5-membered alkyl bridge which        may contain 1 to 2 heteroatoms, or    -   R⁴ and R³ or R⁵ and R³ together denote a saturated or        unsaturated C₃-C₄-alkyl bridge, which may optionally contain 1        heteroatom,    -   and    -   A₁ and A₂ which may be identical or different represent —CH═ or        —N═, preferably —N═, in which a compound of formula II

wherein

R¹-R⁵ and A₁, A₂ have the stated meaning and

R⁶ denotes C₁-C₄-alkyl,

a) is hydrogenated with hydrogen in the presence of a hydrogenationcatalyst and

b) a copper, iron or vanadium compound is added,

in which steps a) and b) may take place simultaneously or successively.

In a preferred process, the hydrogenation of the compound of formula IIis carried out directly in the presence of the hydrogenation catalystand the copper, iron or vanadium compound to form the compound offormula I.

In a particularly preferred process, after the first hydrogenation stepa), first of all the intermediate product of formula III is obtained,which may optionally be isolated,

and is then further reduced in the presence of a hydrogenation catalystand a copper, iron or vanadium compound to form a compound of formula I

Also preferred is a process in which the hydrogenation catalyst isselected from the group consisting of rhodium, ruthenium, iridium,platinum, palladium and nickel, preferably platinum, palladium and Raneynickel. Platinum is particularly preferred. Platinum may be used inmetallic form or oxidised form as platinum oxide on carriers such ase.g. activated charcoal, silicon dioxide, aluminium oxide, calciumcarbonate, calcium phosphate, calcium sulphate, barium sulphate,titanium dioxide, magnesium oxide, iron oxide, lead oxide, lead sulphateor lead carbonate and optionally additionally doped with sulphur orlead. The preferred carrier material is activated charcoal, silicondioxide or aluminium oxide.

Preferred copper compounds are compounds in which copper assumesoxidation states I or II, for example the halides of copper such as e.g.CuCl, CuCl₂, CuBr, CuBr₂, CuI or CuSO₄. Preferred iron compounds arecompounds wherein iron assumes oxidation states II or III, for examplethe halides of iron such as e.g. FeCl₂, FeCl₃, FeBr₂, FeBr₃, FeF₂ orother iron compounds such as e.g. FeSO₄, FePO₄ or Fe(acac)₂.

Preferred vanadium compounds are compounds wherein vanadium assumes theoxidation states 0, II, III, IV or V, for example inorganic or organiccompounds or complexes such as e.g. V₂O₃, V₂O₅, V₂O₄, Na₄VO₄, NaVO₃,NH₄VO₃, VOCl₂, COCl₃, VOSO₄, VCl₂, VCl₃, vanadiumoxobis(1-phenyl-1,3-butanedionate), vanadium oxotriisopropoxide,vanadium(III)acetylacetonate [V(acac)₃] orvanadium(IV)oxyacetylacetonate [VO(acac)₂].Vanadium(IV)oxyacetylacetonate [VO(acac)₂] is particularly preferred

The copper, iron or vanadium compound may be used either directly at thestart of the hydrogenation or after the formation of the intermediate offormula (III), as preferred.

Also preferred is a process wherein the amount of added hydrogenationcatalyst is between 0.1 and 10 wt.-% based on the compound of formula(II) used.

Also preferred is a process wherein the amount of copper, iron orvanadium compound used is between 0.01 and 10 wt.-% based on thecompound of formula (II) used.

Also preferred is a process wherein the reaction is carried out in asolvent selected from the group consisting of dipolar, aprotic solvents,for example dimethylformamide, dimethylacetamide, N-methylpyrrolidinone,dimethylsulphoxide or sulpholane; alcohols, for example methanol,ethanol, 1-propanol, 2-propanol, the various isomeric alcohols of butaneand pentane; ethers, for example diethyl ether, methyl-tert.-butylether,tetrahydrofuran, 2-methyltetrahydrofuran, dioxane or dimethoxyethane;esters, for example ethyl acetate, 2-propylacetate or 1-butylacetate;ketones, for example acetone, methylethylketone or methylisobutylketone;carboxylic acids, for example acetic acid; apolar solvents, for exampletoluene, xylene, cyclohexane or methylcyclohexane, as well asacetonitrile, methylene chloride and water.

The solvents may also be used as mixtures.

Also preferred is a process wherein the reaction temperature is between0° C. and 150° C., preferably between 20° C. and 100° C.

Also preferred is a process wherein the hydrogen pressure is 1 bar to100 bar.

The invention further relates to a compound of formula (III)

wherein R¹ to R⁵ may have the stated meaning.

Preferred compounds of formula (III) are those wherein A₁ and A₂ areidentical and denote —N═.

The reactions are worked up by conventional methods e.g. by extractivepurification steps or precipitation and crystallisation methods.

The compounds according to the invention may be present in the form ofthe individual optical isomers, mixtures of the individual enantiomers,diastereomers or racemates, in the form of the tautomers as well as inthe form of the free bases or the corresponding acid addition salts withacids—such as for example acid addition salts with hydrohalic acids, forexample hydrochloric or hydrobromic acid, or organic acids, such as forexample oxalic, fumaric, diglycolic or methanesulphonic acid.

Examples of alkyl groups, including those which are part of othergroups, are branched and unbranched alkyl groups with 1 to 12 carbonatoms, preferably 1-6, particularly preferably 1-4 carbon atoms, such asfor example: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,nonyl, decyl and dodecyl. Unless otherwise stated, the above-mentioneddesignations propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyland dodecyl include all the possible isomeric forms. For example theterm propyl includes the two isomeric groups n-propyl and iso-propyl,the term butyl includes n-butyl, iso-butyl, sec. butyl and tert.-butyl,the term pentyl includes isopentyl, neopentyl etc.

In the above-mentioned alkyl groups one or more hydrogen atoms mayoptionally be replaced by other groups. For example these alkyl groupsmay be substituted by fluorine. It is also possible for all the hydrogenatoms of the alkyl group to be replaced.

Examples of alkyl bridges, unless otherwise stated, are branched andunbranched alkyl groups with 2 to 5 carbon atoms, for example ethylene,propylene, isopropylene, n-butylene, iso-butyl, sec. butyl andtert.-butyl etc. bridges. Particularly preferred are ethylene, propyleneand butylene bridges. In the above-mentioned alkyl bridges 1 to 2 Catoms may optionally be replaced by one or more heteroatoms selectedfrom among oxygen, nitrogen or sulphur.

Examples of alkenyl groups (including those which are part of othergroups) are branched and unbranched alkylene groups with 2 to 12 carbonatoms, preferably 2-6 carbon atoms, particularly preferably 2-3 carbonatoms, provided that they have at least one double bond. The followingare mentioned by way of example: ethenyl, propenyl, butenyl, pentenyletc. Unless otherwise stated, the above-mentioned designations propenyl,butenyl etc. include all the possible isomeric forms. For example theterm butenyl includes 1-butenyl, 2-butenyl, 3-butenyl,1-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl,2-methyl-2-propenyl and 1-ethyl-1-ethenyl.

In the above-mentioned alkenyl groups, unless otherwise described, oneor more hydrogen atoms may optionally be replaced by other groups. Forexample these alkyl groups may be substituted by the halogen atomfluorine. It is also possible for all the hydrogen atoms of the alkenylgroup to be replaced.

Examples of alkynyl groups (including those which are part of othergroups) are branched and unbranched alkynyl groups with 2 to 12 carbonatoms, provided that they have at least one triple bond, for exampleethynyl, propargyl, butynyl, pentynyl, hexynyl etc., preferably ethynylor propynyl.

In the above-mentioned alkynyl groups, unless otherwise described, oneor more hydrogen atoms may optionally be replaced by other groups. Forexample these alkyl groups may be fluorosubstituted. It is also possiblefor all the hydrogen atoms of the alkynyl group to be replaced.

The term aryl denotes an aromatic ring system with 6 to 14 carbon atoms,preferably 6 or 10 carbon atoms, preferably phenyl, which, unlessotherwise described, may for example carry one or more of the followingsubstituents: OH, NO₂, CN, OMe, —OCHF₂, —OCF₃, halogen, preferablyfluorine or chlorine, C₁-C₁₀-alkyl, preferably C₁-C₅-alkyl, preferablyC₁-C₃-alkyl, particularly preferably methyl or ethyl, —O—C₁-C₃-alkyl,preferably —O-methyl or —O-ethyl, —COOH, —COO—C₁-C₄-alkyl, preferably—O-methyl or —O-ethyl, —CONH₂.

Examples of cycloalkyl groups are cycloalkyl groups with 3-12 carbonatoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl or cyclooctyl, preferably cyclopropyl, cyclopentyl orcyclohexyl, while each of the above-mentioned cycloalkyl groups mayoptionally also carry one or more substituents, for example: OH, NO₂,CN, OMe, —OCHF₂, —OCF₃ or halogen, preferably fluorine or chlorine,C₁-C₁₀-alkyl, preferably C₁-C₅-alkyl, preferably C₁-C₃-alkyl,particularly preferably methyl or ethyl, —O—C₁-C₃-alkyl, preferably—O-methyl or —O-ethyl, —COOH, —COO—C₁-C₄-alkyl, preferably —COO-methylor —COO-ethyl or —CONH₂. Particularly preferred substituents of thecycloalkyl groups are ═O, OH, methyl or F.

Examples of cycloalkenyl groups are cycloalkyl groups with 3-12 carbonatoms, which have at least one double bond, for example cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, preferablycyclopropenyl, cyclopentenyl or cyclohexenyl, while each of theabove-mentioned cycloalkenyl groups may optionally also carry one ormore substituents.

“═O” denotes an oxygen atom linked by a double bond.

Examples of heterocycloalkyl groups are, unless otherwise described inthe definitions, 3- to 12-membered, preferably 5-, 6- or 7-membered,saturated or unsaturated heterocycles, which may contain nitrogen,oxygen or sulphur as heteroatoms, for example tetrahydrofuran,tetrahydrofuranone, γ-butyrolactone, α-pyran, γ-pyran, dioxolane,tetrahydropyran, dioxane, dihydrothiophene, thiolane, dithiolane,pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline,imidazolidine, tetrazole, piperidine, pyridazine, pyrimidine, pyrazine,piperazine, triazine, tetrazine, morpholine, thiomorpholine, diazepan,oxazine, tetrahydro-oxazinyl, isothiazole and pyrazolidine, preferablymorpholine, pyrrolidine, piperidine or piperazine, while the heterocyclemay optionally carry substituents, for example C₁-C₄-alkyl, preferablymethyl, ethyl or propyl.

Examples of polycycloalkyl groups are optionally substituted, bi-, tri-,tetra- or pentacyclic cycloalkyl groups, for example pinane,2,2,2-octane, 2,2,1-heptane or adamantane. Examples of polycycloalkenylgroups are optionally bridged and/or substituted, 8-membered bi-, tri-,tetra- or pentacyclic cycloalkenyl groups, preferably bicycloalkenyl ortricycloalkenyl groups, if they contain at least one double bond, forexample norbornene.

Examples of spiroalkyl groups are optionally substituted spirocyclicC₅-C₁₂ alkyl groups.

Halogen generally denotes fluorine, chlorine, bromine or iodine,preferably fluorine, chlorine or bromine, particularly preferablychlorine.

The substituent R¹ may represent a group selected from the groupconsisting of chlorine, fluorine, bromine, methanesulphonyl,ethanesulphonyl, trifluoromethanesulphonyl and para-toluenesulphonyl,preferably chlorine.

The substituent R² may represent hydrogen or C₁-C₃-alkyl, preferablyhydrogen.

The substituent R³ may represent hydrogen,

-   -   or a group selected from the group consisting of optionally        substituted C₁-C₁₂-alkyl, C₂-C₁₂-alkenyl, C₂-C₁₂-alkynyl, and        C₆-C₁₄-aryl, preferably phenyl, or a group selected from the        group consisting of optionally substituted and/or bridged        C₃-C₁₂-cycloalkyl, preferably cyclopentyl, C₃-C₁₂-cycloalkenyl,        C₇-C₁₂-polycycloalkyl, C₇-C₁₂-polycycloalkenyl,        C₅-C₁₂-spirocycloalkyl and saturated or unsaturated        C₃-C₁₂-heterocycloalkyl, which contains 1 to 2 heteroatoms.

The substituents R⁴, R⁵ may be identical or different and may representhydrogen,

-   -   or optionally substituted C₁-C₆-alkyl,    -   or R⁴ and R⁵ together represent a 2- to 5-membered alkyl bridge        which may contain 1 to 2 heteroatoms,    -   or R⁴ and R³ or R⁵ and R³ together represent a saturated or        unsaturated C₃-C₄-alkyl bridge, which may optionally contain 1        heteroatom.

A₁ and A₂ which may be identical or different represent —CH═ or —N═,preferably —N═.

R⁶ may represent a C₁-C₄-alkyl, preferably methyl or ethyl.

The compound of formula (II) may be prepared according to methods knownfrom the literature, for example analogously to the syntheses describedin WO 03/020722.

The compounds of general formula (I) may be prepared inter aliaanalogously to the following examples of synthesis. These Examples are,however, intended only as examples of procedures to illustrate theinvention, without restricting it to their content. The generalsynthesis is shown in Scheme (1).

Synthesis of(7R)-2-chloro-8-cyclopentyl-7-ethyl-5-hydroxy-7,8-dihydro-5H-pteridin-6-one

30 g (84.2 mmol) of 1 are dissolved in 300 ml of tetrahydrofuran and 3 gPt/C (5%) are added. The reaction mixture is hydrogenated for 5 h at 35°C. and a hydrogen pressure of 4 bar. The catalyst is filtered off andwashed with approx. 30 ml of tetrahydrofuran. The filtrate isconcentrated by evaporation under reduced pressure. 25.6 g of product 2are obtained as a yellow solid.

¹H-NMR (400 MHZ) (DMSO_(d6)): δ11.05 (bs 1H); 7.85 (s 1H); 4.47-4.45 (dd1H); 4.16-4.08 (t 1H); 1.95-1.67 (m 10H); 0.80-0.73 (t 3H)

Synthesis of(7R)-2-chloro-8-cyclopentyl-7-ethyl-7,8-dihydro-5H-pteridin-6-one

5.22 g (17.6 mmol) of 2 are dissolved in 55 ml of tetrahydrofuran. 520mg Pt—C (5%) and 250 mg vanadium(IV)oxyacetylacetonate are added. Thereaction mixture is hydrogenated for 6 hours at 20° C. and a hydrogenpressure of 4 bar. The catalyst is filtered off and washed with approx.15 ml of tetrahydrofuran. The filtrate is concentrated by evaporationunder reduced pressure.

5.0 g of product 3 are obtained as a yellow powder.

¹H-NMR (400 MHz) (DMSO_(d6)): δ11.82 (bs 1H); 7.57 (s 1H); 4.24-4.21 (dd1H); 4.17-4.08 (m 1H); 1.97-1.48 (m 10H); 0.80-0.77 (t 3H).

Synthesis of:(7R)-2-chloro-8-cyclopentyl-7-ethyl-7,8-dihydro-5H-pteridin-6-one

70 g Pt/C (5%) are added to a solution of 700 g (1.96 mol) of 1 in 700ml of tetrahydrofuran. The reaction mixture is hydrogenated for 2.5hours at 35° C. and a hydrogen pressure of 4 bar until the hydrogenuptake has stopped. The autoclave is opened and 35 gvanadium(IV)oxyacetylacetonate are added. The mixture is hydrogenatedfor a further 2.5 hours at 35° C. and a hydrogen pressure of 4 bar. Itis filtered and the residue is washed with tetrahydrofuran. The filtrateis concentrated by evaporation under reduced pressure. The residue isdissolved in 2.75 L acetone and precipitated by the addition of an equalamount of demineralised water. The solid is suction filtered and washedwith an acetone/water mixture (1:1), then with tert.-butylmethylether.After drying 551 g of product 3 are obtained.

Synthesis of:(7R)-2-chloro-8-cyclopentyl-7-ethyl-7,8-dihydro-5H-pteridin-6-one

30 g (84 mmol) of 1 are dissolved in 300 ml of tetrahydrofuran. 3 g Pt/C(5%) and 1.5 g vanadium(IV)oxyacetylacetonate are added. The reactionmixture is hydrogenated for 24 hours at 35° C. and a hydrogen pressureof 4 bar until the reaction is complete. It is filtered, the residue iswashed with tetrahydrofuran and the filtrate is concentrated byevaporation under reduced pressure. The residue is dissolved in 118 mlacetone and precipitated by the addition of an equal amount ofdemineralised water. The solid is suction filtered and washed with anacetone/water mixture (1:1) and then with tert.-butylmethylether. Afterdrying 18 g of product 3 are obtained.

Synthesis of:(7R)-2-chloro-7-ethyl-8-isopropyl-7,8-dihydro-5H-pteridin-6-one

10 g (316 mmol) of 4 are dissolved in 800 ml of tetrahydrofuran and 200ml isopropanol. 10 g Pt/C (5%) and 5 g vanadium(IV)oxyacetylacetonateare added. The reaction mixture is hydrogenated for 24 hours at 35° C.and a hydrogen pressure of 4 bar until the reaction is complete. It isfiltered and the filtrate is evaporated down until crystallisation setsin. 150 ml isopropanol are added and the suspension is heated to 70-80°C. until fully dissolved. After the addition of 600 ml demineralisedwater the product is brought to crystallisation. It is suction filteredand washed with demineralised water. After drying 68 g of product 5 areobtained.

¹H-NMR (400 MHz) (DMSO_(d6)): δ10.81 (bs 1H); 7.56 (s 1H); 4.37-4.24 (m2H); 1.89-1.65 (m 2H); 1.34-1.31 (m 6H); 0.80-0.73 (t 3H)

1. A process for preparing compounds of the formula I

wherein R¹ denotes a group selected from the group consisting ofchlorine, fluorine, bromine, methanesulphonyl, ethanesulphonyl,trifluoromethanesulphonyl, para-toluenesulphonyl, CH₃S(═O)— andphenylS(═O)—, R² denotes hydrogen or C₁-C₃-alkyl, R⁴, R⁵ which may beidentical or different denote hydrogen or optionally substitutedC₁-C₆-alkyl, or R⁴ and R⁵ together denote a 2- to 5-membered alkylbridge, which may contain 1 to 2 heteroatoms, and R⁴ and R³ or R⁵ and R³together denote a saturated or unsaturated C₃-C₄-alkyl bridge, which mayoptionally contain 1 heteroatom, and A₁ and A₂ are different and denote—CH═ or —N═, comprising a) hydrogenating with hydrogen in the presenceof a hydrogenation catalyst and a compound of formula II

wherein R¹ to R⁵, A₁ and A₂ have the meanings given above and R⁶ denotesC₁-C₄-alkyl, and b) adding a copper, iron or vanadium compound, whereinin which steps a) and b) may take place simultaneously or successively.2. The process according to claim 1, wherein in step b) a coppercompound is added.
 3. The process according to claim 1, wherein in stepb) an iron compound is added.
 4. The process according to claim 1,wherein in step b) a vanadium compound is added.
 5. The processaccording to claim 1 wherein steps a) and b) are carried outsuccessively.
 6. The process according to claim 5, wherein that afterthe first step a) the intermediate product of formula III is firstobtained, which may optionally be isolated,

and after the subsequent step b) a compound of formula I is obtained. 7.The process according to claim 1, wherein steps a) and b) are carriedout simultaneously.
 8. The process according to claim 1, wherein thehydrogenation catalyst is selected from the group consisting of rhodium,ruthenium, iridium, platinum, palladium and nickel.
 9. The processaccording to claim 1, wherein the amount of hydrogenation catalyst addedis between 0.1 and 10 wt.-%, based on the compound of formula (II) used.10. The process according to claim 1, wherein the amount of copper, ironor vanadium compound added is between 0.01 and 10 wt.-%, based on thecompound of formula (II) used.
 11. The process according to claim 1,wherein the reaction is carried out in a solvent or mixture of solventsselected from the group consisting of dipolar, aprotic solvents,alcohols, ethers, esters, carboxylic acids, apolar solvents,acetonitrile, methylene chloride and water.
 12. The process according toclaim 1, wherein the reaction temperature is between 0° C. and 150° C.13. The process according to claim 1, wherein the hydrogen pressure isfrom 1 bar to 100 bar.
 14. A process for preparing compounds of theformula I

wherein R¹ denotes a group selected from the group consisting ofchlorine, fluorine, bromine, methanesulphonyl, ethanesulphonyl,trifluoromethanesulphonyl, para-toluenesulphonyl, CH₃S(═O)— andphenylS(═O)—, R² denotes hydrogen or C₁-C₃-alkyl, R⁴, R⁵ which may beidentical or different denote hydrogen or optionally substitutedC₁-C₆-alkyl, or R⁴ and R⁵ together denote a 2- to 5-membered alkylbridge, which may contain 1 to 2 heteroatoms, and R⁴ and R³ or R⁵ and R³together denote a saturated or unsaturated C₃-C₄-alkyl bridge, which mayoptionally contain 1 heteroatom, and A₁ and A₂ are different, denote—CH═ or —N═, comprising hydrogenating a compound of formula III withhydrogen in the presence of a hydrogenation catalyst and a copper, ironor vanadium compound

wherein R¹ to R⁵ and A₁, A₂ have the meanings given above in this claim.